Screening for Lung Cancer: Challenges for Thoracic Surgery
Brendon M. Stiles
Nasser K. Altorki
David F. Yankelevitz
Lung cancer is a global health burden and is among the most common and deadly of all malignancies worldwide. In the United States, lung cancer accounts for 25% of all cancer deaths, exceeding deaths from breast, colon, and prostate cancer combined.27 Approximately 89% of individuals with lung cancer die of the disease. This is primarily because a large proportion of patients with lung cancer present with locally advanced or metastatic disease. Screening of high-risk individuals, by identifying more patients with resectable and potentially curable disease, may reduce the overall death rate from lung cancer. In the United States, three randomized trials, conducted in the late 1970s, examined the value of plain chest radiography with or without sputum cytology for lung cancer screening in men who were active or former smokers.15,35,63 These studies failed to demonstrate a decrease in lung cancer related mortality in the screened populations. The results of these trials are in contrast to the results of five more recent case-controlled studies from Japan demonstrating a benefit associated with screening.37,39,49,53,66 Owing to these conflicting results, the American Cancer Society (ACS) and the U.S. Preventative Services Task Force (USPSTF) do not recommend either for or against screening. They instead suggest that interested individuals discuss the pros and cons of screening with their physicians. More recently, the introduction of multislice low-dose computed tomography (CT) technology has renewed interest in screening for lung cancer. It has been established that CT is more sensitive than chest x-ray (CXR) for the detection of small pulmonary nodules and that the majority of small cancers detected by CT are not detected by plain chest radiography.22,23,55 Nonetheless, debate continues over the value of CT screening in reducing lung cancer–related mortality, both on a societal and an individual patient basis. What is certain is that the use of CT for early detection of lung cancer has presented the thoracic surgeon with several important challenges, most notably the clinical evaluation of individuals with subcentimeter lung nodules who are frequently referred for surgical management. In this chapter, we briefly discuss previous and current studies of lung cancer screening, including promising future screening modalities. We also describe our current approach for the evaluation of small pulmonary nodules referred for surgical management.
History of Lung Cancer Screening
Interest in screening high-risk patients for lung cancer was sparked when the association between cigarette smoking and lung cancer was first appreciated by Doll and Hill in the 1950s.11 The first mass screening project was conducted by Brett in London from 1960 to 1964.6 Although not a randomized trial, 55,034 men were assigned to undergo either CXR every 6 months for 3 years (the screened group) or a single CXR at the beginning of the study, followed by a repeat CXR at the end of the 3-year period (the “unscreened” group). At the end of the 3-year period, more lung cancers were detected in the screened group than in the “unscreened” group (132 versus 96 cases). In ad- dition, resectability was enhanced in the screened group. Despite these findings, lung cancer–specific mortality was not different between the two groups.
In the 1970s, the National Cancer Institute (NCI) funded three randomized trials (Table 102-1) for lung cancer screening using both CXR and sputum cytology.15,35,63 Two of these trials (the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Cancer Center [MSKCC] trial) focused on the value of the addition of sputum cytology to annual CXRs. In the MSKCC study, patients were randomized to annual CXR alone or annual CXR plus sputum cytology assessment every 4 months. The same number of cancers were detected in both groups. No difference was detected in resectability rates or lung cancer–specific mortality. This screening protocol was also utilized in the Johns Hopkins Lung Project randomized trial, with similar results. No difference in the number of lung cancers or lung cancer–specific mortality was detected between the two groups.
The Mayo Lung Project focused on the combined impact of CXR and sputum cytology in screening for lung cancer. Patients were randomized to undergo CXR and sputum cytology assessment every 4 months for 6 years (the screened group) or given the usual recommendation of the Mayo Clinic—namely, to undergo both of these examinations annually, but without reminders sent to these individuals (the “unscreened” group). With over 10,000 participants, the study was powered to show a 50% reduction in lung cancer–related mortality. After a median follow-up period of 3 years, more lung cancers were detected in the screened group than in the unscreened group. In addition, the resectability rate in the screened group was significantly
higher. Nonetheless, there was no statistically significant difference in lung cancer–specific mortality between the two populations. However, there has been concern that the failure to show a benefit from screening may have stemmed from the lack of contrast between the screen and control groups. Notably, over 50% of individuals in the unscreened group had CXRs during the course of the study, and approximately 25% of participants in the screened group failed to comply with the screening regimen. Other concerns relate to the high rate of competing causes of death and the overall lack of power to demonstrate a realistic benefit associated with screening.
higher. Nonetheless, there was no statistically significant difference in lung cancer–specific mortality between the two populations. However, there has been concern that the failure to show a benefit from screening may have stemmed from the lack of contrast between the screen and control groups. Notably, over 50% of individuals in the unscreened group had CXRs during the course of the study, and approximately 25% of participants in the screened group failed to comply with the screening regimen. Other concerns relate to the high rate of competing causes of death and the overall lack of power to demonstrate a realistic benefit associated with screening.
Table 102-1 Historical Lung Cancer Screening Trials Involving Chest X-ray and Sputum Sampling | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A similar screening trial was conducted by Kubik and Polak28 (Table 102-1) in the late 1970s in Czechoslovakia; it also focused on the combined effects of CXR and sputum cytology examination for lung cancer screening. In this trial, participants in the screened group underwent CXR and evaluation of sputum cytology every 6 months for 3 years, while those in the “unscreened” group had an initial CXR and sputum cytology examination, both of which were repeated at the end of the 3-year period. After the initial screening period, both groups underwent annual CXR and sputum assessment for an additional 3 years. Once again, more lung cancers were diagnosed in the screened group than in the “unscreened” group (39 versus 27 cases). However, there was no difference in lung cancer–specific mortality between the two groups.
Computed Tomography Screening Trials
In the 1990s, increased resolution and data-acquisition speeds of modern CT scanners rekindled interest in screening for lung cancer. Initial findings from Henschke and colleagues21,22,23 of the Early Lung Cancer Action Project (ELCAP) showed that in a high risk population, CT was superior to CXR in detecting lung nodules. Notably, 2.7% of those enrolled had lung cancer; the great majority of these lesions were stage I. Within the initial ELCAP patient population, 27 screen-diagnosed lung cancers were found at baseline screenings; 96% were resectable.21 A subsequent report by the I-ELCAP (International ELCAP) group addressed overall curability estimated through 10-year survival rates of patients found to have stage I lung cancer by CT screening.26 The authors reported an estimated 88% 10-year survival rate, markedly higher than survival rates predicted by the current staging system or among those presenting as a result of symptoms. They inferred that because CT screening leads to early detection of lung cancer and those lung cancers found as a result of CT screening are curable, CT screening leads to a reduction in lung cancer mortality. Several other groups have also evaluated CT screening for lung cancer. A recently published review by Black and colleagues5 identified 12 studies, of which two were randomized while the other 10 had no comparator group. Significant variability existed in the study populations and in the definition of a positive finding in each. Nevertheless, the percentage of positive screenings ranged from 5.1% to 51%. From baseline screenings, 1.8% to 18% of positive findings led to a diagnosis of cancer. The majority of the tumors were in stage I (53%–100%), with a high resectability rate (>78%). Only one of the studies reported 5-year survival: 76% for patients with cancer detected at baseline screening and 65% for patients with cancer detected at annual repeat scanning.54
However, the data on CT screening are far from conclusive. In fact, much like the CXR and sputum screening trials, none of the CT trials have yet shown an advantage to survival in screened patient populations versus unscreened populations. This and other shortcomings were highlighted by a recently published multicenter study by Bach and colleagues,2 which reviewed the findings from CT screening of 3,246 high-risk patients. In this study, there was no evidence of a decline in the number of patients with advanced diagnoses or of deaths from lung cancer in the screened groups. Despite this failure to demonstrate a difference in mortality, there was a threefold increase in individuals diagnosed with lung cancer and a tenfold increase in patients undergoing lung resection (compared with expected cases). The authors used these data to argue that CT screening is vulnerable to overdiagnosis and that it may therefore be exposing patients to unnecessary surgery. They concluded that CT screening may not meaningfully reduce the risk of dying from lung cancer.
Table 102-2 Results of Baseline Lung Cancer Screening Using Computed Tomography Scans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
An important limitation of this study was the relatively short median follow-up time of only 3.9 years. This may have prevented the detection of any benefit from screening. For most screening studies, any potential benefit or mortality impact is not likely to emerge before at least 4 to 5 rounds of screening have been completed. Furthermore, one of the three studies included in the analysis did not require the exclusion of symptomatic individuals. This may have resulted in the inclusion of patients with symptoms of preexisting lung cancer, possibly violating the core concept of screening. Exclusion of symptomatic patients from the analysis could have substantially altered the results.
The Statistical Arguments
The efficacy of screening in reducing cancer-specific mortality may be confounded by lead-time, length, and overdiagnosis biases. Although the statistical arguments may be examined from many different vantage points and are sometimes difficult to interpret, they have been well described previously by Strauss.59 We highlight some of those arguments here.
In all screening trials, one must distinguish lead time from lead-time bias. The success of any screening program depends on a lead time in diagnosis and treatment. This in and of itself does not present a problem. Bias can arise when short-term survival rates are used to assess the value of screening in populations with and without lead time. Lead-time bias should not affect resectability or, more important, curability. In the subpopulations of patients with lung cancer in the older screening trials, there were increased proportions of 5-year survivors in the screen-detected cases compared with those in the control arms in both the Mayo and Czech studies.15,28 The survival curves never converged, suggesting that screening did increase the cure rate of patients with cancer. These mature data imply that lead-time bias does not explain differences in survival between those groups. The I-ELCAP investigators’ effort to estimate 10-year survival rates, rather than shorter-term rates, was also an attempt to avoid any possible lead-time bias.26 The I-ELCAP strategy to avoid lead-time bias was to estimate the cure rate. This occurs at the plateau phase of the survival cure, its asymptote, at which point the additional deaths that occur are due to competing causes. Length bias essentially refers to the tendency of screening to lead to the diagnosis of slower-growing cancers more frequently in the baseline round, as these tumors could have been present for a considerable time prior to the screening study. For tumors detected only on repeat rounds of screening, this is far less of a concern. A review of the Mayo data, however, demonstrates that survival rates were only slightly better in the prevalence cases when compared with the incidence cases (40% versus 33%)—those diagnosed at repeat screening.59 In the I-ELCAP data, no distinction was made in survival rates between the prevalence and incidence groups.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
